Diastereoselective Synthesis of the Acyl Side-Chain and Amino Acid (2S,3R)-3-Hydroxy-3-Methylproline Fragments of Polyoxypeptin A

Abstract

Synthesis of the acyl side-chain and amino acid (2S,3R)-3-hydroxy-3-methylproline units of the potent depsipeptide poly­oxypeptin A, is described. Key intermediates were secured via dia­stereoselective addition involving a homoenolate ion and allylation of an aminoketone, respectively.

Key words

asymmetric aldol - asymmetric dihydroxylation - polyoxypeptin A - homoenolate - ketone allylation - amino acids

References

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6

Procedure for the Synthesis of Enamine 10.
(-)-Sparteine (773 mg, 3.3 mmol) and n-BuLi (2.1 mL, 1.6 M in hexane) in toluene (20 mL) were cooled to -78 °C under nitrogen and pre-cooled 9 (0.784 g, 2.35 mmol) in toluene (15 mL) was added. The bright yellow mixture was stirred for 45 min and Et₂AlCl (3.5 mL, 1 M in hexane) was added, and the color faded to pale yellow. After 1 h, propionaldehyde (1.5 mL, 20.8 mmol) was added and the mixture was stirred for 12 h at this temperature. Then, MeOH (20 mL) was added and the reaction warmed to r.t. After warming to r.t., HCl (20 mL, 1 M) was added and the mixture extracted with EtOAc (2 × 50 mL). The organic extracts were washed with brine (20 mL), dried (Na₂SO₄), concentrated and purified by flash chromatography.

8

Compound 17: ¹H NMR (300 MHz, CDCl₃): δ = 0.72 (3 H, d, J = 6.8 Hz), 0.73 (3 H, q, J = 6.8 Hz, 8.2 Hz), 0.80 (3 H, t, J = 7.4 Hz), 0.93 (2 H, m), 1.10 (1 H, m), 1.11 (1 H, m), 1.17 (1 H, m), 1.22 (1 H, m), 1.24 (3 H, t, J = 7.1 Hz), 1.32 (1 H, m), 1.35 (1 H, m), 1.50 (3 H, s), 1.52 (1 H, m), 1.63 (1 H, m), 1.69 (1 H, m), 1.85 (1 H, m), 3.40 (1 H, m), 3.56 (1 H, d, J = 2.5 Hz), 3.61 (1 H, s), 4.19 (2 H, q, J = 7.1 Hz). ¹³C NMR (75 MHz, CDCl₃): δ = 173.59, 96.78, 79.40, 75.68, 61.83, 38.25, 35.82, 31.04, 31.02, 28.47, 25.16, 24.64, 19.14, 18.64, 14.23, 11.60, 8.81. [α]_D ²⁰ +20.4 (c 0.6, CHCl₃). HRMS: m/z calcd for C₆H₁₁NO₃ [M - H₂O]: 298.2144; found: 298.2151.

14

The diastereomeric excess of amino alcohols 24a and 24b were determined by chiral HPLC analysis (conditions: column: Daicel OD; mobile phase: hexane-i-PrOH = 9:1; detection UV: 254 nm; flow rate: 1 mL/min; t _R(min): 5.06 (24a, syn isomer), 3.58 (24a, anti isomer); 27.00 (24b, syn isomer), 19.66 (24b, anti isomer).

16

Procedure for the Synthesis of 24a.
Allylmagnesium bromide (1 M solution in Et₂O, 5 mL) was added dropwise to a well-stirred solution of (+)-B-methoxy-diisopinocampheylborane (5 mmol in 30 mL Et₂O) at 0 °C. Following completion of addition, the reaction mixture was vigorously stirred for 1 h at 25 °C. The solution was removed under vacuum and the residue was extracted with anhyd pentane. Evaporation of pentane gave the (Ipc)₂BAll which was used in the next step. Aminoketone 21a (4 mmol in 10 mL CH₂Cl₂) was added into the Ipc₂BAll solution (in 40 mL anhyd Et₂O) at 25 °C and then stirred overnight. The reaction was quenched with MeOH and treated with Et₃N (1.39 mL) and 30% H₂O₂ (10 mmol, 0.68 mL). Standard work-up and purification of the resulting crude product by chromatography on silica gel gave the corresponding homo-allylic alcohol 24a in 96% yield.

17

Compound 20a: ¹H NMR (300 MHz, CDCl₃): δ = 0.63 (6 H, q, J = 7.6 Hz), 0.99 (9 H, t, J = 7.9 Hz), 1.37 (9 H, s), 1.57 (3 H, m), 2.14-2.29 (2 H, m), 3.96-4.04 (1 H, m), 4.31 (1 H, t, J = 10.7 Hz), 4.50-4.84 (2 H, m), 5.13 (2 H, m), 5.80 (1 H, m), 7.40 (2 H, t, J = 7.2 Hz), 7.53 (1 H, t, J = 8.0 Hz), 8.05 (2 H, t, J = 8.0 Hz). ¹³C NMR (75 MHz, CDCl₃): δ = 166.7, 155.3, 133.3, 132.8, 130.1, 129.8, 128.2, 118.9, 79.1, 64.5, 55.4, 46.2, 28.3, 25.1, 7.1, 6.7. [α]_D ²⁰ +15.4 (c 10.0, CHCl₃).

20

Compound 28: ¹H NMR (300 MHz, CDCl₃): δ = 3.73 (3 H, s), 3.48 (1 H, s), 3.22-3.27 (1 H, m), 2.97-2.90 (1 H, m), 2.50 (1 H, br s), 1.96-1.76 (2 H, m), 1.56 (3 H, s), 0.93 (9 H, t, J = 7.8 Hz), 0.57 (6 H, q, J = 7.8 Hz). ¹³C NMR (75 MHz, CDCl₃): δ = 171.62, 82.61, 71.90, 51.62, 44.86, 42.17, 25.94, 6.86, 6.36.

22

Compound 19: ¹H NMR (500 MHz, D₂O): δ = 3.86 (1 H, s), 3.54 (1 H, ddd), 3.45 (1 H, ddd), 2.15 (2 H, m), 1.60 (3 H, s). ¹³C NMR (125 MHz, D₂O): δ = 171.16, 78.81, 70.06, 43.69, 39.82, 24.22. HRMS: m/z calcd for C₆H₁₁NO₃: 145.0738; found: 145.0715. [α]_D ²⁰ - 41 (c 0.3, H₂O).